Polyethylenimine-mediated impairment of mitochondrial membrane potential, respiration and membrane integrity: implications for nucleic acid delivery and gene therapy

Mitochondrion. 2012 Jan;12(1):162-8. doi: 10.1016/j.mito.2011.08.013. Epub 2011 Sep 10.


The 25 kDa branched polyethylenimine (PEI) is a highly efficient synthetic polycation used in transfection protocols, but also triggers mitochondrial-mediated apoptotic cell death processes where the mechanistic issues are poorly understood. We now demonstrate that PEI in a concentration- and time-dependent manner can affect functions (membrane potential, swelling and respiration) and ultrastructural integrity of freshly isolated rat liver mitochondria. The threshold concentration for detection of PEI-mediated impairment of rat liver mitochondrial functions is 3 μg/mL, however, lower PEI levels still exert some effects on mitochondrial morphology and respiration, and these may be related to the inherent membrane perturbing properties of this polycation. The PEI-mediated mitochondrial swelling phase is biphasic, with a fast decaying initial period (most prominent from 4 μg/mL PEI) followed by a slower, linear swelling response. The slow phase is presumably the result of a time-dependent transition permeability opening in mitochondria initially resistant to swelling/depolarization, but may further be related to PEI-induced nanoscale structural defects and/or formation of pores in the outer membrane. Respiration assessments further suggested that PEI in the presence of exogenous ADP behaves in a similar fashion to a slow-acting inhibitory compound. PEI further shows an uncoupling property that is detectable at low respiration rates. The relevance of these findings to PEI-mediated initiation of intrinsic apoptotic pathway is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Respiration / drug effects*
  • Dose-Response Relationship, Drug
  • Genetic Therapy
  • Hepatocytes / drug effects
  • Hepatocytes / ultrastructure
  • Liver / drug effects
  • Male
  • Membrane Potential, Mitochondrial / drug effects*
  • Mitochondria / drug effects
  • Mitochondria / ultrastructure
  • Mitochondrial Membranes / drug effects*
  • Mitochondrial Membranes / physiology
  • Nucleic Acids / genetics
  • Nucleic Acids / metabolism
  • Polyethyleneimine / toxicity*
  • Rats
  • Rats, Wistar


  • Nucleic Acids
  • Polyethyleneimine